The mechanism by which glucocorticoids program the cardiometabolic impairment is not completely understood. Although one final common pathway may involve the kidney, the decrease in nephron number, by itself, does not explain the elevation in blood pressure. In this project we will address an additional mechanism by which prenatal steroids cause cardiometabolic impairment, i.e., a functional alteration in the local adipose tissue renin angiotensin system (RAS) and that these alterations are amplified by obesity, a second hit that tilts the balance towards insulin resistance and further elevations in blood pressure. The working hypothesis is that antenatal steroid exposure has a programming effect on white adipose tissue development and function and predisposes the individual for developing insulin resistance and hypertension. We further hypothesize that 1) antenatal steroid exposure alters the function of a local renin-angiotensin system (RAS) within the white adipose tissue, 2) the abnormal adipose tissue RAS function predisposes the individual for developing cardiovascular and metabolic alterations, 3) Obesity exaggerates the functional derangement of adipose tissue, thus increasing the impact antenatal steroid exposure has on cardiovascular and metabolic regulation. Obesity will be induced using a standard ruminant formula, thus fat composition of the diet is removed as a confounding factor. Sheep of both sexes will be randomly allocated to be fed 100% of recommended nutritional allowance or ad libitum for three months. Given the increasing incidence of obesity and the mounting evidence for a developmental origin of cardiovascular disease, the studies proposed will determine if obesity, a modifiable risk factor, has a significant contribution in the development of cardiovascular diseases in animals exposed antenatally to steroids. We will test these hypotheses with the following specific aims: Specific Aim 1: To study the effects of antenatal glucocorticoid exposure on the expression of critical components of the RAS and inflammatory mediators in white adipose tissue depots (subcutaneous, omental and perirenal) and the consequences these changes have on adipose tissue function. Specific Aim 2: To determine which component(s) of the adipose tissue RAS mediate(s) the cardiometabolic dysregulation in animals exposed antenatally to glucocorticoids. Specific Aim 3: To study the mechanism by which superimposed obesity exaggerates the cardiovascular and metabolic abnormalities induced by antenatal steroid exposure.